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KAIST's Mathematician Reveals the Mechanism for Sustaining Biological Rhythms
Our bodies have a variety of biological clocks that follow rhythms or oscillations with periods ranging from seconds to days. For example, our hearts beat every second, and cells divide periodically. The circadian clock located in the hypothalamus generates twenty-four hour rhythms, timing our sleep and hormone release. How do these biological clocks or circuits generate and sustain the stable rhythms that are essential to life? Jae Kyoung Kim, who is an assistant professor in the Department of Mathematical Sciences at KAIST, has predicted how these biological circuits generate rhythms and control their robustness, utilizing mathematical modeling based on differential equations and stochastic parameter sampling. Based on his prediction, using synthetic biology, a research team headed by Matthew Bennett of Rice University constructed a novel biological circuit that spans two genetically engineered strains of bacteria, one serves as an activator and the other as a repressor to regulate gene expression across multiple cell types, and found that the circuit generates surprisingly robust rhythms under various conditions. The results of the research conducted in collaboration with KAIST (Korea Institute of Science and Technology), Rice University, and the University of Houston were published in Science (August 28, 2015 issue). The title of the paper is "Emergent Genetic Oscillations in a Synthetic Microbial Consortium" . The top-down research approach, which focuses on identifying the components of biological circuits, limits our understanding of the mechanisms in which the circuits generate rhythms. Synthetic biology, a rapidly growing field at the interface of biosciences and engineering, however, uses a bottom-up approach. Synthetic biologists can create complex circuits out of simpler components, and some of these new genetic circuits are capable of fluctuation to regulate gene production. In the same way that electrical engineers understand how an electrical circuit works as they construct batteries, resistors, and wires, synthetic biologists can understand better about biological circuits if they put them together using genes and proteins. However, due to the complexity of biological systems, both experiments and mathematical modeling need to be applied hand in hand to design these biological circuits and understand their function. In this research, an interdisciplinary approach proved that a synthetic intercellular singling circuit generates robust rhythms to create a cooperative microbial system. Specifically, Kim's mathematical analysis suggested, and experiments confirmed, that the presence of negative feedback loops in addition to a core transcriptional negative feedback loop can explain the robustness of rhythms in this system. This result provides important clues about the fundamental mechanism of robust rhythm generation in biological systems. Furthermore, rather than constructing the entire circuit inside a single bacterial strain, the circuit was split among two strains of Escherichia coli bacterium. When the strains were grown together, the bacteria exchanged information, completing the circuit. Thus, this research also shows how, by regulating individual cells within the system, complex biological systems can be controlled, which in turn influences each other (e.g., the gut microbiome in humans). ### Ye Chen, a graduate student in Bennett's laboratory at Rice University, and Jae Kyoung Kim, an assistant professor at KAIST and a former postdoctoral fellow at Ohio State University, are the lead authors of the paper. The co-authors are Rice graduate student Andrew Hirning and Krešimir Josic?, a professor of mathematics at the University of Houston. Bennett is the Assistant Professor of the Biochemistry and Cell Biology Department at Rice University. About the researcher: While Jae Kyoung Kim is a mathematician, he has also solved various biological puzzles in collaboration with various experimental laboratories of Matthew Bennett at Rice University, David Virshup at Duke and the National University of Singapore, Carla Finkielstein at Virginia Polytechnic Institute and State University, Choo-Gon Lee at the Florida State University, Seung-Hee Yoo at the Medical School of the University of Texas, Toru Takumi at RIKEN Brain Science Institute, and Travis Wager at Pfizer Inc. He has used non-linear dynamics and stochastic analysis to understand the function of biochemical networks in biological systems. In particular, he is interested in mechanisms generating and regulating biological rhythms. Picture 1: This schematic image is the design of a biological circuit between two strains of bacteria and the part of differential equations used to understand the function of the biological circuit. Picture 2: The core transcriptional negative feedback loop and additional negative feedback loop in the biological circuit (picture 1) generate robust rhythms. The snapshots correspond the red dots in the time series graph.
Nature Biotechnology Nominates Sang Yup Lee of KAIST for Top 20 Translational Researchers of 2014
Nature Biotechnology, recognized as the most prestigious journal in the field of biotechnology, has released today its list of the Top 20 Translational Researchers of 2014. Distinguished Professor Sang Yup Lee of the Department of Chemical and Biomolecular Engineering at KAIST (Korea Advanced Institute of Science and Technology) ranked seventh in the list. He is the only Asian researcher listed. The journal, in partnership with IP Checkups, a patent analytics firm, presents an annual ranking of researchers based on their paper and patent output. The list includes, among others, each researcher’s most-cited patent in the past five years and their H index, a measurement to evaluate the impact of a researcher’s published work utilizing citation analysis. (More details can be found at http://www.nature.com/bioent/2015/150801/full/bioe.2015.9.html.) American institutions made up the majority of the list, with 18 universities and research institutes, and the remainder was filled by KAIST in Korea and the Commonwealth Scientific and Industrial Research Organization (CSIRO) in Australia. Globally known as a leading researcher in systems metabolic engineering, Professor Lee has published more than 500 journal papers and 580 patents. He has received many awards, including the Citation Classic Award, Elmer Gaden Award, Merck Metabolic Engineering Award, ACS Marvin Johnson Award, SIMB Charles Thom Award, POSCO TJ Park Prize, Amgen Biochemical Engineering Award, and the Ho Am Prize in Engineering.
Dr. Hyundoo Hwang Receives a Tenured Position at Monterrey Institute of Technology and Higher Education
Hyundoo Hwang, a former graduate student in the Department of Bio & Brain Engineering at KAIST, has been granted a tenured position at the Monterrey Institute of Technology and Higher Education (ITSEM), Mexico. Dr. Hwang received his bachelor’s, master’s, and doctoral degree at KAIST and started his professorship at Ulsan National Institute of Science & Technology (UNIST) in Korea. He continued his research in the United States as a professor at Georgia Institute of Technology. He has been acknowledged for the development of an advanced nanotechnology for the diagnosis of rare diseases and research in cell signals. He is one of the leading researchers in an international research project in microelectromechanical systems (MEMS) with participation by researchers from over ten countries. He has been active in commercializing biosensor technology in the U.S. and Mexico. Since its establishment in 1943, ITSEM has grown to 33 campuses in 25 cities in Mexico. It is the largest university in Latin America with over 90,000 students (47% of its graduate students has oversea research experience). It recruits over 5,000 international students and professors every year. Dr. Hwang will begin teaching at ITSEM as a professor in the Department of Biomedical Engineering (Ingeniería Biomédica) this fall. He will also conduct research in nano- and micro-technology as a member of Sensors and Devices research group. Professor Gwang Hyun Cho, head of KAIST's Department of Bio and Brain Engineering said that Dr. Hwang’s tenure professorship at ITSEM demonstrated that the academic program at KAIST—from undergraduate to doctoral—was on par with the international standard. He hoped that more talents from the department would seek academic careers in internationally renowned universities around the world.
A Technology Holding Company Establishes Two Companies Based on Technologies Developed at KAIST
Mirae Holdings is a technology holding company created by four science and technology universities, KAIST, DIGIST (Daegu Gyeongbuk Institute of Science and Technology), GIST (Gwangju Institute of Science and Technology), and UNIST (Ulsan National Institute of Science and Technology) in 2014 to commercialize the universities’ research achievements. The company identifies promising technologies for commercialization, makes business plans, establishes venture capitals, and invests in startup companies. Over the past year, Mirae Holdings has established two venture companies based on the technologies developed at KAIST. In September 2014, it founded Cresem Inc., a company used the anisotropic conductive film (ACF) bonding technology, which was developed by Professor Kyung-Wook Paik of the Material Science and Engineering Department at KAIST. Cresem provides a technology to bond electronic parts ultrasonically. The company is expected to have 860,000 USD worth of sales within the first year of its launching. Last June, Mirae Holdings created another company, Doctor Kitchen, with the technology developed by Professor Gwan-Su Yi of the Bio and Brain Engineering Department at KAIST. Doctor Kitchen supplies precooked food, which helps diabetic patients regulate their diet. The company offers a personalized diet plan to customers so that they can effectively manage their disease and monitor their blood sugar level efficiently. The Chief Executive Officer of Mirae Holdings, Young-Ho Kim, said, “We can assist KAIST researchers who aspire to create a company based on their research outcomes through various stages of startup services such as making business plans, securing venture capitals, and networking with existing businesses.” Young-Ho Kim (left in the picture), the Chief Executive Officer of Mirae Holdings, holds a certificate of company registration with Sang-Min Oh (right in the picture), the Chief Executive Officer of Cresem. Young-Ho Kim (left in the picture), the Chief Executive Officer of Mirae Holdings, holds a certificate of company registration with Jae-Yeun Park (right in the picture), the Chief Executive Officer of Dr. Kitchen.
KAIST to support the Genetic Donguibogam Research Project for global market entry of a new natural drug produced by Green Cross Corporation HS
In the wake of the spread of the Middle East Respiratory Syndrome (MERS), sales of immune-enhancing products in Korea such as red and white ginseng have risen dramatically. Ginseng is one of Korea’s major health supplement it exports, but due to the lack of precise scientific knowledge of its mechanism, sales of ginseng account for less than 2% of the global market share. The Genetic Donguibogam Research Project represents a group of research initiatives to study genes and environmental factors that contribute to diseases and to discover alternative treatments through Eastern medicine. The project is being led by KAIST’s Department of Bio & Brain Engineering Professor Do-Heon Lee. Professor Lee and Chief Executive Officer Young-Hyo Yoo of Green Cross Corporation HS, a Korean pharmaceutical company, signed a memorandum of understanding (MOU), as well as a non-disclosure agreement (NDA) to develop a naturally derived drug with an enhanced ginsenoside, pharmacological compounds of ginseng, for the global market entry of BST204 on June 10, 2015. Donguibogam is the traditional Korean source for the principles and practice of Eastern medicine, which was compiled by the royal physician Heo Jun and first published in 1613 during the Joseon Dynasty of Korea. Cooperating with Green Cross Co., HS, KAIST researchers will use a multi-component, multi-target (MCMT)-based development platform to produce the new natural drug, BST204. This cooperation is expected to assist the entry of the drug into the European market. Green Cross Co., HS has applied a bio-conversion technique to ginseng to develop BST204, which is a drug with enhanced active constituent of aginsenosides. The drug is the first produced by any Korean pharmaceutical company to complete the first phase of clinical trials in Germany and is about to start the second phase of trials. Professor Do-Heon Lee, the Director of the project said, “Genetic Donguibogam Research Project seeks to create new innovative healthcare material for the future using integrated fundamental technologies such as virtual human body computer modelling and multi-omics to explain the mechanism in which natural ingredients affect the human body.” He continued, “Especially, by employing the virtual human body computer modelling, we can develop an innovative new technology that will greatly assist Korean pharmaceutical industry and make it the platform technology in entering global markets.” Young-Hyo Yoo, the CEO of Green Cross Co., HS, said, “For a new naturally derived drug to be acknowledged in the global market, such as Europe and the US, its mechanism, as well as its effectiveness and safety, should be proven. However, it is difficult and costly to explain the mechanism in which the complex composition of a natural substance influences the body. Innovative technology is needed to solve this problem.” Professor Do-Heon Lee (left in the picture), the Director of Genetic Donguibogam Research Project, stands abreast Young-Hyo Yoo (right in the picture), the CEO of Green Cross Co., HS.
Professor Sang-Yup Lee Receives the Order of Service Merit Red Stripes from the Korean Government
The government of the Republic of Korea named Professor Sang-Yup Lee of the Department of Chemical and Bio-molecular Engineering at KAIST as the fiftieth recipient of the Order of Service Merit Red Stripes on May 19, 2015. This medal is awarded to government employees, officials, and teachers in recognition of their contributions to public services including education. Professor Lee is regarded as a leading scientist in the field of metabolic engineering, genomics, proteomics, metabolomics, and bioinformatics on microorganism producing various primary and secondary metabolites. He contributed significantly to the advancement of bio-based engineering research in Korea. In addition, his research in microorganism metabolic engineering propelled him to the front of his field, making him the world’s founder of systems metabolic engineering, inventing numerous technologies in strain development. Professor Lee has received many patent rights in bioprocess engineering. While at KAIST, he applied for 585 patents and registered 227 patents. In particular, he has applied for 135 patents and registered 99 patents in the past five years, successfully turning research results into commercial applications. Professor Lee said, “I’m glad to contribute to the development of Korean science and technology as a researcher and teacher. I would like to share this honor with my students, master’s and doctoral students in particular, because without their support, it wouldn’t have been possible to pull off the highest level of research results recognized by this medal.”
Mystery in Membrane Traffic How NSF Disassembles Single SNAR Complex Solved
KAIST researchers discovered that the protein N-ethylmaleimide-sensitive factor (NSF) unravels a single SNARE complex using one round ATP turnover by tearing the complex with a single burst, contradicting a previous theory that it unwinds in a processive manner. In 2013, James E. Rothman, Randy W. Schekman, and Thomas C. Südhof won the Nobel Prize in Physiology or Medicine for their discoveries of molecular machineries for vesicle trafficking, a major transport system in cells for maintaining cellular processes. Vesicle traffic acts as a kind of “home-delivery service” in cells. Vesicles package and deliver materials such as proteins and hormones from one cell organelle to another. Then it releases its contents by fusing with the target organelle’s membrane. One example of vesicle traffic is in neuronal communications, where neurotransmitters are released from a neuron. Some of the key proteins for vesicle traffic discovered by the Nobel Prize winners were N-ethylmaleimide-sensitive factor (NSF), alpha-soluble NSF attachment protein (α-SNAP), and soluble SNAP receptors (SNAREs). SNARE proteins are known as the minimal machinery for membrane fusion. To induce membrane fusion, the proteins combine to form a SNARE complex in a four helical bundle, and NSF and α-SNAP disassemble the SNARE complex for reuse. In particular, NSF can bind an energy source molecule, adenosine triphosphate (ATP), and the ATP-bound NSF develops internal tension via cleavage of ATP. This process is used to exert great force on SNARE complexes, eventually pulling them apart. However, although about 30 years have passed since the Nobel Prize winners’ discovery, how NSF/α-SNAP disassembled the SNARE complex remained a mystery to scientists due to a lack in methodology. In a recent issue of Science, published on March 27, 2015, a research team, led by Tae-Young Yoon of the Department of Physics at the Korea Advanced Institute of Science and Technology (KAIST) and Reinhard Jahn of the Department of Neurobiology of the Max-Planck-Institute for Biophysical Chemistry, reports that NSF/α-SNAP disassemble a single SNARE complex using various single-molecule biophysical methods that allow them to monitor and manipulate individual protein complexes. “We have learned that NSF releases energy in a burst within 20 milliseconds to “tear” the SNARE complex apart in a one-step global unfolding reaction, which is immediately followed by the release of SNARE proteins,” said Yoon. Previously, it was believed that NSF disassembled a SNARE complex by unwinding it in a processive manner. Also, largely unexplained was how many cycles of ATP hydrolysis were required and how these cycles were connected to the disassembly of the SNARE complex. Yoon added, “From our research, we found that NSF requires hydrolysis of ATPs that were already bound before it attached to the SNAREs—which means that only one round of an ATP turnover is sufficient for SNARE complex disassembly. Moreover, this is possible because NSF pulls a SNARE complex apart by building up the energy from individual ATPs and releasing it at once, yielding a “spring-loaded” mechanism.” NSF is a member of the ATPases associated with various cellular activities family (AAA+ ATPase), which is essential for many cellular functions such as DNA replication and protein degradation, membrane fusion, microtubule severing, peroxisome biogenesis, signal transduction, and the regulation of gene expression. This research has added valuable new insights and hints for studying AAA+ ATPase proteins, which are crucial for various living beings. The title of the research paper is “Spring-loaded unraveling of a single SNARE complex by NSF in one round of ATP turnover.” (DOI: 10.1126/science.aaa5267) Youtube Link: https://www.youtube.com/watch?v=FqTSYHtyHWE&feature=youtu.be Picture 1. Working model of how NSF/α-SNAP disassemble a single SNARE complex Picture 2. After neurotransmitter release, NSF disassembles a single SNARE complex using a single round of ATP turnover in a single burst reaction.
KVIP Opened in Pangyo
KAIST has opened the KAIST Venture Innovation Program (KVIP) in its Center for Industry Outreach, designed for executive and high-ranking officers of venture companies. Located in Pangyo Techno Valley, KAIST’s Center for Industry Outreach was established in collaboration with the government of Gyeonggi Province to support venture companies in Pangyo for business management training, venture networking, and university-industry cooperation. The program will be held every Monday for 12 weeks from April 13 to July 6 in KAIST’s Center for Industry Outreach. This executive education program mainly focuses on solving problems that arise when a medium-sized venture company is in the course of growing into a global corporation. The program is divided into four courses which will cover business management, competition in the global market, transformation of a company, and technological innovation. Professors from various departments at KAIST will give lectures on their fields. Professor Jaeseung Jeong from the Bio and Brain Engineering Department, Professor Hoi-Jun Yoo from the Electrical Engineering Department, Professor Sangmin Bae from the Industrial Design Department, and Professor Kwangjae Sung from the Business and Technology Management Department will each deliver lectures on brain engineering, semiconductor, design, and restructuring. Industry experts are also invited to give talks, including Dr. Dae-Gyu Byun, the Chief Executive Officer and President of HUMAX Electronics, Dr. Gwang-Cheol Choi, the Chief Executive Officer of SK Engineering & Construction, Mr. Il-young Kim, the former Chief Executive Officer of KT, Dr. Jae-hoon Jeong, the President of the Korea Institute for the Advancement of Technology (KIAT), Dr. Intak Bae, the Chief Executive Officer of Summit Partners, and Mr. Kyung-taek Kwak, a film director. The department has started recruiting first round applicants for the program, targeting executive and high-ranking officers of middle-sized venture companies. The details of the program can be found on its website, kvip.kaist.ac.kr.
Professor Sangyong Jon Appointed Fellow of AIMBE
Professor Sangyong Jon of the Department of Biological Sciences at KAIST has been appointed a member of the American Institute for Medical and Biological Engineering (AIMBE) fellowship. Established in 1991, AIMBE is a non-profit organization based in Washington, D.C., representing 50,000 individuals and the top 2% of medical and biological engineers. AIMBE provides policy advice and advocacy for medical and biological engineering for the benefit of humanity. It has had about 1,500 fellows over the past 25 years. Among the members, only 110 are non-American nationalities. Following the appointment of Dr. Hae-Bang Lee, the former senior researcher at the Korean Research Institute of Chemical Technology, and Distinguished Professor Sang Yup Lee of the Department of Chemical and Biomolecular Engineering at KAIST, Professor Jon is the third Korean to become an AIMBE fellow. He had an induction ceremony for the appointment of his fellowship at the AIMBE’s Annual Event held on March 15-17, 2015 in Washington, D.C. An authority on nanomedicine, Professor Jon has developed many original technologies including multi-functional Theranostics nano particles for the diagnosis and treatment of diseases. He received the Most Cited Paper Award from Theranostics, an academic journal specialized in nanomedicine, last February. Additionally, Professor Jon is a leading researcher in the field of translational medicine, using a multi-disciplinary, highly collaborative, “Bench to Bedside” approach for disease treatment and prevention. He created a biotechnology venture company and transferred research developments to the industry in Korea.
Professor Sang Yup Lee Appointed Founding Board Member of Cell Systems
Distinguished Professor Sang Yup Lee of the Department of Chemical and Biomolecular Engineering at KAIST has been appointed a member of the founding editorial board of the newly established journal Cell Systems. Cell Systems will be a sister journal of Cell, one of the three most prestigious scientific journals along with Nature and Science, that publishes a wide range of papers on biological engineering. The first issue of Cell Systems will be published this July. Cell Systems plans to publish innovative discoveries, reviews of various research instruments, and research findings on integrated and quantified systems in the field of biology. Professor Lee is a pioneer in metabolic engineering of microorganism with a focus on biopolymers and metabolites production. He is the editor-in-chief of Biotechnology Journal and serves on the editorial board of numerous international journals. He is also a member of the Global Agenda Council of the World Economic Forum and the Presidential Advisory Committee on Science and Technology in Korea. Professor Lee said, “Cell Systems will present research findings that discuss whole biological systems methodically.” He continued, “I hope many research findings of Korean scholars will be published in Cell Systems, which will become a representative journal of systems biology and systems biological engineering.”
Professor Kwang-Hyun Cho Recognzied by "Scientist of the Month" Award
Professor Kwang-Hyun Cho of KAIST’s Department of Bio and Brain Engineering received the “Scientist of the Month” award in February 2015 from the Ministry of Science, ICT, and Future Planning of the Republic of Korea and the National Research Foundation of Korea. The award was in recognition of Professor Cho’s contribution to the advanced technique of controlling the death of cancer cells based on systems biology, a convergence research in information technology (IT) and biotechnology. Professor Cho has published around 140 articles in international journals, including 34 papers in renowned science journals such as Nature, Science, and Cell in the past three years. His work also includes systems biology textbooks and many entries in international academic encyclopaedia. His field, systems biology, is a new biological research paradigm that identifies and controls the fundamental principles of organisms on a systems level. A well-known tumour suppressor protein, p53, is known to suppress abnormal cell growth and promote apoptosis of can cells, and thus was a focus of research by many scientists, but its effect has been insignificant and brought many side effects. This was due to the complex function of p53 that controls various positive and negative feedbacks. Therefore, there was a limit to understanding the protein with the existing biological approach. However, Professor Cho found the kinetic change and function of p53 via a systems biology approach. By applying IT technology to complex biological networks, he also identified the response to stress and the survival and death signal transduction pathways of cardiomyocytes and developed new control methods for cancer cells. Professor Cho said, “This award served as a momentum to turn over a new leaf.” He added, “I hope convergence research such as my field will bring more innovative ideas on the boundaries of academia.”
The Bio-Synergy Research Center, KAIST, Hosts an Annual Meeting
The Ministry of Science, ICT and Future Planning of the Republic of Korea founded the Bio-Synergy Research Center (BSRC) at KAIST in 2013 to develop source technology and generate new knowledge by conducting convergence research projects in natural resources with information technology (IT) and biotechnology. The BSRC hosted an annual meeting on November 21, 2014, at the KAIST campus and reviewed the progress it made this year with the participation of President Steve Kang of KAIST, Commissioner Young-min Kim of KIPO, and Director Doheon Lee of BSRC. The Korean Intellectual Property Office (KIPO) provided BSRC with its database in Korean traditional medicine that includes a vast amount of information about disease symptoms, native medicinal herbs and plant extracts, prescriptions, and chemical compounds used for medication. The database, “Compound Combination-Oriented Natural Product Database with Unified Terminology (COCUNUT),” holds approximately one million data sets in four major categories: prescriptions, medicinal resources, medicine components and functions, and diseases. Based on COCUNUT, BSRC has been working on the standardization of Korean traditional medicine such as the development of data mapping and text mining technology and the analysis of big data in accordance with the said categories. Using IT and biotechnology, the center has also created a virtual human body to explain how traditional medicine works in human body, thereby contributing to the development of new natural materials for medicine.
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